Tratamiento de inducción de anticuerpos para los receptores de trasplante pulmonar
Resumen
Antecedentes
El trasplante pulmonar se ha convertido en una opción de tratamiento valiosa y bien aceptada para la mayoría de las enfermedades pulmonares terminales. Los receptores de trasplante pulmonar están en riesgo de rechazo del órgano trasplantado, y necesitan inmunosupresión de por vida. Las pruebas claras son esenciales para identificar una estrategia óptima, segura y efectiva de tratamiento inmunosupresor para los receptores de trasplante pulmonar. Aún no se ha logrado un consenso en cuanto al uso de anticuerpos inmunosupresores contra los linfocitos T para la inducción posterior al trasplante pulmonar.
Objetivos
Se intentaron evaluar los efectos beneficiosos y perjudiciales de la inducción de anticuerpos inmunosupresores contra los linfocitos T con ATG, ALG, IL‐2RA, alemtuzumab, o muromonab‐CD3 en receptores de trasplante pulmonar.
Métodos de búsqueda
Se realizaron búsquedas en el registro especializado del Grupo Cochrane de Riñón (Cochrane Renal Group) hasta el 4 de marzo de 2013 a través del contacto con el coordinador de búsqueda de ensayos y mediante términos de búsqueda relevantes para esta revisión. Los estudios contenidos en el registro especializado se identifican a través de estrategias de búsqueda diseñadas específicamente para CENTRAL, MEDLINE y EMBASE.
Criterios de selección
Se incluyeron todos los ensayos controlados aleatorios (ECA) que compararon la inducción de anticuerpos inmunosupresores monoclonales y policlonales contra los linfocitos T para receptores de trasplante pulmonar. Un criterio de inclusión dispuso que todos los participantes debían haber recibido el mismo tratamiento inmunosupresor de mantenimiento en cada estudio.
Obtención y análisis de los datos
Tres autores extrajeron los datos. Se calcularon los cocientes de riesgos (CR) para los datos dicotómicos y las diferencias de medias (DM) para los datos continuos con intervalos de confianza (IC) del 95%. El riesgo de sesgo metodológico se evaluó mediante la herramienta Cochrane del riesgo de sesgo y se realizaron análisis secuenciales de los ensayos para evaluar el riesgo de errores aleatorios (intervención del azar).
Resultados principales
La revisión incluyó seis ECA (que representaron a un total de 278 adultos receptores de trasplante pulmonar) que evaluaron el uso de inducción de anticuerpos contra los linfocitos T. La evaluación de los estudios incluidos halló que todos presentaban un riesgo alto de sesgo.
Se realizaron comparaciones de la inducción de anticuerpos policlonales o monoclonales contra los linfocitos T versus ninguna inducción (tres estudios, 140 participantes); anticuerpos policlonales contra los linfocitos T versus ninguna inducción (tres estudios, 125 participantes); antagonistas de receptores de interleucina 2 (IL‐2RA) versus ninguna inducción (un estudio, 25 participantes); anticuerpos policlonales contra los linfocitos T versus muromonab‐CD3 (un estudio, 64 participantes); anticuerpos policlonales contra los linfocitos T versus IL‐2RA (tres estudios, 100 participantes). En general, no se encontró ninguna diferencia significativa entre las intervenciones en cuanto a la mortalidad, el rechazo agudo, los efectos adversos, la infección, la neumonía, la infección por citomegalovirus, el síndrome de bronquiolitis obliterante, la enfermedad linfoproliferativa postrasplante, o el cáncer.
Se encontró una diferencia significativa en los resultados en un estudio que comparó globulina antitimocito versus muromonab‐CD3 en relación con los eventos adversos (25/34 [74%] versus 12/30 [40%]; CR 1,84; IC del 95%: 1,13 a 2,98). Estos datos indicaron que la globulina antitimocito aumentó la aparición de eventos adversos. Sin embargo, el análisis secuencial de los ensayos halló que no se había alcanzado el tamaño necesario de información y la curva Z acumulativa no cruzó los límites de monitorización del consumo de alfa en las secuencias de los ensayos.
Ninguno de los estudios informó calidad de vida o lesión renal. Los análisis secuenciales de los ensayos indicaron que ninguno de los metanálisis logró los tamaños necesarios de información y las curvas Z acumulativas no cruzaron los límites de monitorización del consumo de alfa en las secuencias de los ensayos, ni alcanzaron el área de futilidad.
Conclusiones de los autores
En esta revisión, no se identificaron efectos beneficiosos ni perjudiciales claros asociados con el uso de inducción de anticuerpos contra los linfocitos T en comparación con ninguna inducción, ni al comparar diferentes tipos de anticuerpos contra los linfocitos T. Se identificaron pocos estudios que investigaban el uso de anticuerpos contra los linfocitos T para la inducción después del trasplante pulmonar, y los números de participantes y resultados también fueron limitados. La evaluación de los estudios incluidos encontró que todos estaban en alto riesgo de sesgo metodológico.
Se necesitan ECA adicionales para realizar una evaluación consistente de los efectos beneficiosos y perjudiciales de la inducción de anticuerpos contra los linfocitos T en receptores de trasplante pulmonar. Los estudios futuros deben estar diseñados y realizados según la metodología para reducir los riesgos de errores sistemáticos (sesgo) y de errores aleatorios (intervención del azar).
PICO
Resumen en términos sencillos
¿El tratamiento de inducción de anticuerpos puede ayudar a reducir el rechazo del órgano en receptores de trasplante pulmonar?
Los pacientes que reciben pulmones trasplantados presentan un riesgo significativo de rechazo del órgano. Para ayudar a reducir el riesgo de rechazo del órgano, se administran anticuerpos contra los linfocitos T (un tipo de leucocito que desempeña una función central en la inmunidad) a los pacientes en las dos primeras semanas después del trasplante. Se han usado varios tipos de anticuerpos, aunque no se conocen los efectos beneficiosos y perjudiciales.
Se evaluó el uso de anticuerpos contra los linfocitos T después del trasplante pulmonar para determinar si este tratamiento es seguro, beneficioso o perjudicial, y qué tipo de anticuerpos funcionan mejor y presentan menos efectos adversos.
Se analizaron seis estudios que investigaron la administración de varios tipos diferentes de tratamiento con anticuerpos en 278 pacientes adultos después del trasplante pulmonar. Se encontraron defectos en los diseños de los estudios que indicaron que los estudios estaban en riesgo de sobrestimar los beneficios y subestimar los efectos perjudiciales.
El análisis comparó varios tipos de anticuerpos, aunque, con una excepción ‐ que la globulina antitimocito pareció aumentar algunos eventos adversos ‐, no se encontró ninguna diferencia significativa en la supervivencia o el rechazo de los pulmones para ninguno de los tratamientos. Hubo cierta incertidumbre acerca de este efecto, ya que el estudio fue demasiado pequeño como para asegurar que los beneficios observados se aplicarían a una población más amplia. No se encontraron diferencias significativas entre los tratamientos en cuanto a la infección, el síndrome de bronquiolitis obliterante, la enfermedad linfoproliferativa postrasplante o el cáncer.
Pocos investigaron el uso de anticuerpos contra los linfocitos T después del trasplante pulmonar, y los mismos incluyeron números pequeños de participantes. Estas limitaciones dieron lugar a que los hallazgos no necesariamente indicaran que no existen diferencias entre las comparaciones en el análisis. Para superar este problema, se necesitan estudios aleatorios más amplios y más consistentes que evalúen los efectos beneficiosos y perjudiciales de los anticuerpos contra los linfocitos T en los pacientes después del trasplante pulmonar.
Authors' conclusions
Summary of findings
| T‐cell antibody induction compared with no antibody induction for lung transplant recipients | ||||||
| Patient or population: lung transplant recipients | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No antibody induction | Antibody induction | |||||
| Mortality | Study population | RR 0.99 | 140 (3) | ⊕⊕⊕⊝ | ||
| 448 per 1000 | 444 per 1000 | |||||
| Moderate | ||||||
| 400 per 1000 | 396 per 1000 | |||||
| Acute rejection grade II or higher | Study population | RR 0.66 | 140 (3) | ⊕⊕⊕⊝ | ||
| 483 per 1000 | 319 per 1000 | |||||
| Moderate | ||||||
| 500 per 1000 | 330 per 1000 | |||||
| Infection | Study population | RR 1.4 | 104 (2) | ⊕⊕⊕⊝ | ||
| 458 per 1000 | 642 per 1000 | |||||
| Moderate | ||||||
| 458 per 1000 | 641 per 1000 | |||||
| Bronchiolitis obliterans syndrome | Study population | RR 0.77 | 140 (3) | ⊕⊕⊕⊝ | ||
| 534 per 1000 | 412 per 1000 | |||||
| Moderate | ||||||
| 400 per 1000 | 308 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹ All studies were assessed to be at high risk of bias using the Cochrane risk of bias tool | ||||||
| Polyclonal T‐cell antibody compared with no antibody induction for lung transplant recipients | ||||||
| Patient or population: lung transplant recipients | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No antibody induction | Polyclonal antibody | |||||
| Mortality | Study population | RR 1.02 | 125 (3) | ⊕⊕⊕⊝ | ||
| 448 per 1000 | 457 per 1000 | |||||
| Moderate | ||||||
| 400 per 1000 | 408 per 1000 | |||||
| Acute rejection grade II or higher | Study population | RR 0.68 | 125 (3) | ⊕⊕⊕⊝ | ||
| 483 per 1000 | 328 per 1000 | |||||
| Moderate | ||||||
| 500 per 1000 | 340 per 1000 | |||||
| Infection | Study population | RR 1.4 | 104 (2) | ⊕⊕⊕⊝ | ||
| 458 per 1000 | 642 per 1000 | |||||
| Moderate | ||||||
| 458 per 1000 | 641 per 1000 | |||||
| Bronchiolitis obliterans syndrome | Study population | RR 0.81 | 125 (3) | ⊕⊕⊕⊝ | ||
| 534 per 1000 | 433 per 1000 | |||||
| Moderate | ||||||
| 400 per 1000 | 324 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹ All studies were assessed to be at high risk of bias using the Cochrane risk of bias tool | ||||||
| IL‐2 receptor antagonist induction compared with no antibody induction for lung transplant recipients | ||||||
| Patient or population: lung transplant recipients | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No antibody induction | IL‐2RA induction | |||||
| Mortality | Study population | RR 0.67 | 25 (1) | ⊕⊕⊕⊝ | ||
| 400 per 1000 | 268 per 1000 | |||||
| Moderate | ||||||
| 400 per 1000 | 268 per 1000 | |||||
| Acute rejection | Study population | RR 1.07 | 25 (1) | ⊕⊕⊕⊝ | ||
| 500 per 1000 | 535 per 1000 | |||||
| Moderate | ||||||
| 500 per 1000 | 535 per 1000 | |||||
| Bronchiolitis obliterans syndrome | Study population | RR 0.33 | 25 (1) | ⊕⊕⊕⊝ | ||
| 400 per 1000 | 132 per 1000 | |||||
| Moderate | ||||||
| 400 per 1000 | 132 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹ All studies were assessed to be at high risk of bias using the Cochrane risk of bias tool | ||||||
| Polyclonal T‐cell antibody induction compared with IL‐2RA induction for lung transplant recipients | ||||||
| Patient or population: lung transplant recipients | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| IL‐2RA induction | Polyclonal antibody induction | |||||
| Mortality | Study population | RR 1.41 | 100 (3) | ⊕⊕⊕⊝ | ||
| 113 per 1000 | 160 per 1000 | |||||
| Moderate | ||||||
| 77 per 1000 | 109 per 1000 | |||||
| Acute rejection | Study population | RR 1.33 | 76 (2) | ⊕⊕⊕⊝ | ||
| 525 per 1000 | 698 per 1000 | |||||
| Moderate | ||||||
| 527 per 1000 | 701 per 1000 | |||||
| Infection | Study population | RR 0.91 | 50 (1) | ⊕⊕⊕⊝ | ||
| 880 per 1000 | 801 per 1000 | |||||
| Moderate | ||||||
| 880 per 1000 | 801 per 1000 | |||||
| Bronchiolitis obliterans syndrome | Study population | RR 1.66 | 76 (2) | ⊕⊕⊕⊝ | ||
| 75 per 1000 | 124 per 1000 | |||||
| Moderate | ||||||
| 87 per 1000 | 144 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹ All studies were assessed to be at high risk of bias using the Cochrane risk of bias tool | ||||||
Background
Description of the condition
Success in lung transplantation has led to wide acceptance of the procedure as a treatment for most end‐stage lung diseases. Over 30,000 lung transplantations have been reported to the International Society for Heart and Lung Transplantation (Christie 2011); and of the more than 2700 lung transplantations reported annually, one year survival is over 80%, and five year survival is 60% (Aurora 2009; Christie 2011).
Long‐term recipient survival after lung transplantation remains suboptimal, mainly due to occurrence of bronchiolitis obliterans syndrome. Bronchiolitis obliterans syndrome and late graft failure are responsible for more than 40% of deaths beyond the first year of transplantation (Christie 2011). Primary risks for developing bronchiolitis obliterans syndrome are acute rejection and lymphocytic bronchitis (Hollmen 2008; Verleden 2009). Lung transplant recipients are also at high risk of developing morbidities that inhibit long‐term survival. Major morbidities in lung transplant recipients five years after transplantation are hypertension (85%), hyperlipidaemia (55%), diabetes mellitus (37%), and kidney dysfunction (36%) (Christie 2011).
Description of the intervention
Immunological rejection of lungs means that transplant recipients are at risk of increased morbidity and reduced survival compared with the general population (Christie 2011; Lechler 2005; Verleden 2009). Finding the most effective immunosuppressive treatment strategy is essential to reduce morbidity and increase survival (Iversen 2009).
Optimally, lung transplant recipients should develop immunological tolerance for grafts without compromising general immunity (Chen 2006). Avoidance of adverse effects associated with immunosuppressive agents, such as kidney and cardiovascular diseases and malignancies enhance patients' survival (Flechner 2008; Hauptman 2005).
Maintenance immunosuppressive therapy for lung transplant recipients often involves three types of drugs directed against the T‐cell activation and proliferation cascade: antiproliferative agents (mycophenolate mofetil or azathioprine), calcineurin inhibitors (tacrolimus or cyclosporin), and steroids (prednisolone) (Iversen 2009). Mammalian target of rapamycin inhibitors (sirolimus or everolimus) may also be used as maintenance immunosuppression (Iversen 2009). The optimal combination and dose of these drugs has been the focus of much debate, especially given that calcineurin inhibitors are highly nephrotoxic, and the prolonged use of steroids causes several complications (Flechner 2008; Iversen 2009). No combination of these maintenance immunosuppressive agents has been completely successful in preventing acute and chronic rejection and graft failure without causing adverse reactions (Iversen 2009).
Antibodies specific for T‐cells ‐ induction therapy ‐ have also been used to prevent rejection (Hachem 2006). The aim of T‐cell specific antibody induction therapy is to deplete circulating T‐cells immediately after transplantation before the full effect of calcineurin inhibitor treatment is achieved, thus diminishing rates of acute rejection following transplantation (Iversen 2009). It has also been suggested that temporary immune system manipulation using antibody induction against T‐cells to enhance graft acceptance may pave the way for long‐term reduction of maintenance immunosuppressive treatment (Chatenoud 2008).
Induction is usually commenced before or at the time of maintenance immunosuppressive therapy, and is typically used for a short period of time to avoid risks of severe infection and sepsis. Induction therapy enables delayed introduction or dose reduction of calcineurin inhibitors (Iversen 2009; Rosenberg 2005).
Several T‐cell specific antibodies have been used. These include polyclonal antibodies of horse or rabbit (antithymocyte globulin (ATG) or antilymphocyte globulin (ALG)), or one of the monoclonal agents specific for the CD3 receptor (muromonab‐CD3), the CD52 surface protein (alemtuzumab), or interleukin‐2 receptor antagonists (IL‐2RA; daclizumab or basiliximab) (Hachem 2006; Hachem 2008; Iversen 2009).
ATG, ALG, muromonab‐CD3, and alemtuzumab tend to eradicate functional T‐cell population from the circulation causing profound immunosuppression. The monoclonal IL‐2RA have been developed to increase immunosuppression specificity, with the aim of potentially avoiding over‐immunosuppression toxicity. The IL‐2RA exerts their effects through binding to the alpha subunit of the interleukin‐2 receptor found only on activated T‐cells. Interleukin‐2 receptor blockade prevents interleukin‐2 receptor‐stimulated clonal expression of the T‐cell (Iversen 2009).
Why it is important to do this review
The International Society for Heart and Lung Transplantation has reported that 50% of all transplant centres use T‐cell antibody induction for lung transplant recipients (Christie 2011; Iversen 2009). Consensus on use of immunosuppressive antibody induction after lung transplantation has not yet been achieved (Hachem 2006; Iversen 2009). To enhance survival, it is essential to establish clear evidence to identify an optimal, safe and effective immunosuppressive treatment strategy for lung transplant recipients.
Objectives
We aimed to assess the benefits and harms of immunosuppressive T‐cell antibody induction with ATG, ALG, IL‐2RA, alemtuzumab, or muromonab‐CD3 for lung transplant recipients.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) assessing immunosuppressive induction with monoclonal or polyclonal antibodies against T‐cells for lung transplant recipients were sought. Quasi‐randomised and non‐randomised controlled studies that were identified were considered only for reporting of harms.
Types of participants
We included all patients who had received their first isolated single or double lung transplantation. Data for adult and paediatric patients were planned to be analysed and reported separately because immunological differences in paediatric patients were expected (Aurora 2009).
Types of interventions
-
Studies comparing any dose and duration of immunosuppressive antibody induction with ATG, ALG, alemtuzumab, muromonab‐CD3, or IL‐2RA versus placebo or no intervention.
-
One class of immunosuppressive T‐cell antibody induction versus another class of immunosuppressive T‐cell antibody induction (e.g. IL‐2RA versus ATG).
-
Immunosuppressive T‐cell antibody preparation versus different formulation of same class antibody preparation (e.g. basiliximab versus daclizumab).
Types of outcome measures
Primary outcomes
-
Mortality
-
Acute rejection (≥ A2) according to the classification of the International Society for Heart and Lung Transplantation (A0 (no rejection), A1 (minimal rejection), A2 (mild rejection), A3 (severe rejection); Stewart 2007). We did not plan to evaluate secondary types of rejection such as airway inflammation related to bronchioles
-
Adverse events. Serious adverse events were defined as any untoward medical occurrence that was life threatening, resulted in death, or persistent or significant disability, or any medical event which might have jeopardised the patient or required intervention/s to prevent it. All other adverse events (any medical occurrence not necessarily having a causal relationship with treatment) were considered as non‐serious (ICH GCP 1996).
Secondary outcomes
-
Quality of life
-
Infection
-
Bronchiolitis obliterans syndrome
-
Post‐transplantation lymphoproliferative disease (PTLD)
-
Cancer
-
Kidney injury requiring haemodialysis.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Renal Group's specialised register to 4 March 2013 through contact with the Trials' Search Co‐ordinator using search terms relevant to this review.
The Cochrane Renal Group’s specialised register contains studies identified from:
-
Quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
-
Weekly searches of MEDLINE OVID SP
-
Handsearching of renal‐related journals and the proceedings of major renal conferences
-
Searching of the current year of EMBASE OVID SP
-
Weekly current awareness alerts for selected renal journals
-
Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about the Cochrane Renal Group.
See Appendix 1 for search terms used in strategies for this review.
Searching other resources
-
Reference lists of pulmonology and transplant textbooks, review articles, and relevant studies
-
Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies
-
Bibliographies of relevant articles
-
US Food and Drug Administration (FDA) and European Medicines Agency (EMA) drug approval reviews
-
The Science Citation Index Expanded (1945 to August 2011) (Royle 2003).
Data collection and analysis
Selection of studies
The search strategy described was used to obtain titles and abstracts of studies that could be relevant to the review. Three authors independently assessed study eligibility. Excluded studies were listed with the reason for exclusion. Disagreements were resolved by discussion or in consultation with a third author. Study authors were contacted if information about methodology or data was unclear or missing.
Data extraction and management
Data extraction was carried out independently by two authors using standard data extraction forms (Higgins 2011; Moher 2009). Studies reported in non‐English language journals were planned to be translated before assessment. Where more than one publication of one study existed, publications were grouped together and the publication with the most complete data were used. Where relevant outcomes were only published in earlier versions we planned to use these data. Any discrepancy between published versions was planned to be highlighted. Any further information required from the original author was requested by written correspondence and any relevant information obtained in this manner was included in the review. Disagreements were resolved by consultation among all authors.
We extracted the following information from each study: first author, country of origin, study design, inclusion and exclusion criteria, number of participants, patient characteristics, study drugs, dose, administration, additional immunosuppression, follow‐up period, primary and secondary outcomes, adverse events, and patients lost to follow‐up.
Assessment of risk of bias in included studies
The following items were independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).
-
Was there adequate sequence generation (selection bias)?
-
Was allocation adequately concealed (selection bias)?
-
Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?
-
Participants and personnel
-
Outcome assessors
-
-
Were incomplete outcome data adequately addressed (attrition bias)?
-
Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
-
Was the study apparently free of other problems that could put it at a risk of bias?
Studies assessed as adequately reporting generation of the allocation sequence, allocation concealment, blinding, outcome data reporting, with no evidence of selective outcome reporting, and without vested interests were considered to be at low risk of bias (Gluud 2006; Kjaergard 2001; Moher 1998; Schulz 1995; Wood 2008). Studies assessed to include one or more unclear or inadequate quality components were considered to be at high risk of bias (Moher 1998; Schulz 1995; Wood 2008). High inter‐rater agreement between blinded and unblinded assessments as well as between independent assessors has been found previously (Gluud 2006; Kjaergard 2001).
Measures of treatment effect
For dichotomous outcomes results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment, the mean difference (MD) were used, or the standardised mean difference (SMD) if different scales had been used (Higgins 2003; Thompson 2002).
Dealing with missing data
-
Contacted original investigators to request missing data.
-
Performed sensitivity analyses to assess how sensitive results were to reasonable changes in the assumptions that are made. We performed worst‐worst case scenario analyses, best‐best case scenario analyses, worst‐best case scenario analyses, and best‐worst case scenario analyses.
Assessment of heterogeneity
Heterogeneity was analysed using a Chi² test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.
Assessment of reporting biases
We planned to construct funnel plots to explore bias if more than 10 studies were included in this review (Egger 1997; Macaskill 2001). However, the small number of included studies (6) meant that this could not be undertaken.
Data synthesis
Data were pooled using the random‐effects model and the fixed‐effect model was used to ensure data robustness.
Subgroup analysis and investigation of heterogeneity
The following subgroup analyses were planned to be undertaken.
-
Individual antibody preparation compared with other classes of antibody preparation (e.g. ATG versus IL‐2RA)
-
Antibody preparation compared to different formulation of same class antibody preparation (e.g. basiliximab versus daclizumab)
-
Comparisons of studies at low risk of bias with studies at high risk of bias
-
Studies with early initiation of calcineurin inhibitor (at the time of transplantation) compared to studies with late initiation of calcineurin inhibitor (one to two weeks after transplantation).
Sensitivity analysis
Zero‐event trials
The principal analysis tool used for this review, Review Manager 5, was not designed to analyse studies with zero events when meta‐analyses are performed as relative risk or odds ratios. It seemed unjustified and unreasonable to exclude zero event studies (Keus 2009) that would potentially create a risk of inflating the magnitude of the pooled treatment effects. We therefore performed a random‐effects meta‐analysis with empirical continuity correction of 0.01 in studies with zero events (Sweeting 2004).
Trial sequential analysis
Trial sequential analysis was conducted because cumulative meta‐analyses carry risks of producing random errors due to sparse data and repetitive testing on accumulating data (Thorlund 2011; TSA 2011; Wetterslev 2008). We calculated the required information size, that is, the number of participants needed in a meta‐analysis to detect or reject a certain intervention effect, to minimise random errors (Wetterslev 2008; Wetterslev 2009). Information size calculation should also account for heterogeneity in the meta‐analysis.
In our meta‐analyses, information size was based on an assumed plausible relative risk reduction of 20% or on the relative risk reduction observed in the included studies assessed as low risk of bias (Wetterslev 2008).
The underlying assumption of trial sequential analysis is that significance testing may be performed each time a new study is added to the meta‐analysis. We planned to add studies according to publication year, and if more than one study was published in a year, to add these in alphabetical order according to the family name of the first author.
The required information size was calculated and the trial sequential alpha‐spending and beta‐spending monitoring boundaries were constructed on the basis of the risk for type I (5%) and type II (20%) errors, nominated relative risk, proportion with the outcome in the control group, and observed heterogeneity (TSA 2011; Wetterslev 2008). These boundaries determined the statistical inference that may be drawn regarding cumulative meta‐analyses not achieving the required information size. If a trial sequential monitoring boundary is crossed before the required information size is reached in a cumulative meta‐analysis, firm evidence may have been established and further studies may be superfluous. Conversely, if the alpha‐ and beta‐spending boundaries are not surpassed, it is probably necessary to continue adding studies to detect or reject a certain intervention effect. Defaults used were: type I error, 5%; type II error, 20%; and adjusted information size for diversity unless otherwise stated (Thorlund 2011; Wetterslev 2008).
Results
Description of studies
Results of the search
The search strategy described identified 134 references, and we found another 12 references from other sources. After exclusions, six studies (nine publications; six peer‐reviewed journal articles, two conference abstracts, and one study from ClinicalTrials.gov) were included in our review. Figure 1 depicts the results of our search strategy.
Study flow diagram
Included studies
We included six single‐centre studies that enrolled 278 participants (Brock 2001; Chaparro 1999; Conte 2010; Hartvig 2008; Mullen 2007; Senn 2001).
Chaparro 1999 (60 participants) compared ALG versus placebo; Hartvig 2008 (44 participants) compared ATG versus no intervention; Brock 2001 (64 participants) compared ATG versus muromonab‐CD3; Mullen 2007 (50 participants) compared ATG versus daclizumab; Senn 2001 (24 participants) compared ATG versus basiliximab; and Conte 2010 (36 participants) randomised participants to three groups: ATG, daclizumab, or no intervention.
We compared T‐cell antibody induction versus no T‐cell antibody induction (3 studies, 140 participants; Chaparro 1999; Conte 2010; Hartvig 2008); polyclonal T‐cell antibody induction versus no T‐cell antibody induction (3 studies, 125 participants; Chaparro 1999; Conte 2010; Hartvig 2008); polyclonal T‐cell antibody induction versus muromonab‐CD3 induction (1 study, 64 participants; Brock 2001); polyclonal T‐cell antibody induction versus IL‐2RA induction (3 studies, 100 participants; Conte 2010; Mullen 2007; Senn 2001); and IL‐2RA induction versus no T‐cell antibody induction (1 study, 25 participants; Conte 2010).
Participants in all included studies were adults. Mean age of the total study population was reported in four studies (range: 49 to 53 years) (Brock 2001; Conte 2010; Hartvig 2008; Mullen 2007). With one possible exception, mean ages of participants in single‐centre study treatment groups were similar (Brock 2001; Hartvig 2008; Mullen 2007). In Conte 2010, the mean ages of participants were 49 years in the daclizumab treatment arm; and 58 years and 53 years in the ATG and control groups respectively.
Five studies reported on numbers of single versus double lung transplant recipients (Brock 2001; Conte 2010; Hartvig 2008; Mullen 2007; Senn 2001). In three studies, more than half were single lung transplantations (Brock 2001; Conte 2010; Hartvig 2008). Mullen 2007 reported that more than 70% were double lung transplantations; all participants in Senn 2001 were double lung transplant recipients (100%). Numbers of single and double lung transplantations were similar among treatment groups in the single‐centre studies.
Brock 2001 and Mullen 2007 examined ATG derived from horse (ATGAM®), Conte 2010 and Hartvig 2008 investigated rabbit ATG (Thymoglobulin®); the type of ATG was unclear in Senn 2001.
Although maintenance immunosuppressive treatments were the same in all studies, immunosuppressive treatments varied. A triple immunosuppression regimen was used in five studies (Brock 2001; Conte 2010; Hartvig 2008; Mullen 2007; Senn 2001); Chaparro 1999 did not report maintenance immunosuppression. Participants in all studies received steroid therapy and calcineurin inhibitors; in four studies, the calcineurin inhibitor was cyclosporin (Brock 2001; Conte 2010; Hartvig 2008; Senn 2001); Mullen 2007 administered either tacrolimus or cyclosporin. Brock 2001 and Hartvig 2008 administered azathioprine as an antiproliferative agent; and mycophenolate mofetil was used in Conte 2010, Mullen 2007 and Senn 2001.
Follow‐up varied from six months (Senn 2001), 12 months (Mullen 2007), 2 years (Chaparro 1999; Conte 2010; Brock 2001) and 8 years (Hartvig 2008).
All included studies were published in English.
Excluded studies
See Characteristics of excluded studies.
We excluded 10 studies after full‐text assessment (AIRSAC Trial 2009; Barlow 2001; Borro 2005; Geldmacher 2001; Jaksch 2011; Lawrence 1989; Lischke 2007; Marom 2001; Meiser 1997; van Loenhout 2010). None of these studies assessed T‐cell antibody induction in randomised settings with the use of concomitant immunosuppression.
Risk of bias in included studies
Overall, study methodology was inadequately reported (Figure 2; Figure 3) and all included studies were assessed to be at high risk of bias (Brock 2001; Chaparro 1999; Conte 2010; Hartvig 2008; Mullen 2007; Senn 2001).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Allocation
Sequence generation allocation using computer‐generated randomisation was reported adequately by Mullen 2007; was unclear in Brock 2001, and was not reported in Chaparro 1999, Conte 2010, Hartvig 2008 or Senn 2001.
Allocation concealment was not reported in any of the included studies.
Blinding
Despite reporting that randomisation was double‐blinded, Chaparro 1999 provided no further information. Neither Brock 2001 nor Senn 2001 reported blinding; and Conte 2010 was not blinded. Two studies reported partial blinding: Hartvig 2008 reported that pathologists who examined transbronchial lung biopsy specimens were blinded to the study drug assignment; participants and outcome assessors were not blinded. Mullen 2007 reported that although study participants were blinded, personnel and outcome assessors were not.
Incomplete outcome data
Outcome data reporting was incomplete in five studies (Brock 2001; Chaparro 1999; Conte 2010; Hartvig 2008; Mullen 2007; Senn 2001), but in four of these, omissions did not put them at risk of bias (Brock 2001; Chaparro 1999; Hartvig 2008; Mullen 2007). Five patients died within 30 days following transplantation (group allocations not clear), and were excluded from the analysis by Conte 2010; hence, data analysis was per‐protocol. Incomplete data was not reported by Senn 2001.
Selective reporting
Although we had access to the Conte 2010 study protocol, we were unable to obtain protocols for the other included studies. However, all reported on expected clinical outcome measures (Brock 2001; Chaparro 1999; Hartvig 2008; Mullen 2007; Senn 2001).
Other potential sources of bias
Mullen 2007 was industry‐sponsored. We identified no other issues that could be construed as imposing risk of bias in four studies (Brock 2001; Chaparro 1999; Conte 2010; Hartvig 2008). Senn 2001 did not appear to have any other potential sources of bias, however this was an abstract‐only report (with no additional data provided) and therefore we have assessed the bias as unclear.
Effects of interventions
See: Summary of findings for the main comparison T‐cell antibody induction compared with no antibody induction for lung transplant recipients; Summary of findings 2 Polyclonal T‐cell antibody compared with no antibody induction for lung transplant recipients; Summary of findings 3 IL‐2 receptor antagonist induction compared with no antibody induction for lung transplant recipients; Summary of findings 4 Polyclonal T‐cell antibody induction compared with interleukin‐2 receptor antagonist induction for lung transplant recipients
Polyclonal or monoclonal T‐cell antibody induction versus no induction
Chaparro 1999 (60 participants) compared ALG versus placebo; Hartvig 2008 (44 participants) compared ATG versus no intervention; Conte 2010 (36 participants) randomised patients to three groups: ATG, daclizumab, or no intervention.
Mortality
There was no significant difference in the number of deaths between patients treated with any kind of antibody induction compared with placebo or no induction (33/82 (40%) versus 26/58 (45%), (Analysis 1.1 (3 studies, 140 participants): RR 0.93, 95% CI 0.67 to 1.27; I² = 0%). Analysis showed that trial sequential monitoring boundaries were not broken by the cumulative Z‐curve, and the required information size of 935 participants was not obtained (Figure 4).
Any induction versus no induction; mortality: trial sequential analysis of the effect of induction versus no induction on mortality based on three studies (140 participants). The required information size of 935 patients was calculated based on type I error of 5%, type II error of 20%, risk reduction of 20%, and information size was adjusted for heterogeneity (I² = 0%)
Acute rejection
Acute rejection was defined as the number of patients who experienced at least one episode of rejection. There was no significant difference in the number of patients experiencing acute rejection between those treated with any kind of antibody induction compared with placebo or no induction (29/82 (35%) versus 28/58 (48%) (Analysis 1.2 (3 studies, 140 participants): RR 0.68, 95% CI 0.33 to 1.41; I² = 62%). Analysis showed that trial sequential monitoring boundaries were not broken by the cumulative Z‐curve, and the required information size of 2200 participants was not obtained.
Adverse events
Hartvig 2008 reported that no other adverse events occurred in any of the treatment groups (Analysis 1.3). Chaparro 1999 and Conte 2010 did not report adverse events. Therefore, only the zero event study (Hartvig 2008) contributed data for analysis, and consequently, a meta‐analysis using zero event correction was not conducted.
Quality of life
Quality of life measures were not reported.
Infection
Infection was defined as the number of patients who experienced at least one episode of infection. There was no significant difference in the number of infections between those treated with any kind of antibody induction compared to placebo or no intervention (36/56 (64%) versus 22/48 (46%) (Analysis 1.4 (2 studies, 104 participants): RR 1.40, 95% CI 0.97 to 2.01; I² = 0%).
Pneumonia (viral, bacterial, or fungal)
Pneumonia was defined as the number of patients who experienced at least one episode of pneumonia. There was no significant difference in the number of patients with pneumonia between those treated with any kind of antibody induction compared with placebo or no induction (33/60 (55%) versus 14/36 (39%), (Analysis 1.5 (2 studies, 96 participants): RR 1.38, 95% CI 0.18 to 10.63; I² = 94%).
Cytomegalovirus infection
There was no significant difference in the number of patients with cytomegalovirus infection between those treated with antibody induction compared with placebo or no induction (25/48 (52%) versus 15/32 (47%), (Analysis 1.6 (2 studies 80 participants): RR 1.14, 95% CI 0.73 to 1.80; I² = 0%).
Bronchiolitis obliterans syndrome
There was no significant difference in the number of patients with bronchiolitis obliterans syndrome between those treated with antibody induction compared with placebo or no induction (30/82 (37%) versus 31/58 (53%), (Analysis 1.7 (3 studies, 140 participants): RR 0.74, 95% CI 0.51 to 1.07; I² = 10%).
Post‐transplantation lymphoproliferative disease
Hartvig 2008 reported no significant difference in the number of patients diagnosed with PTLD between those treated with any kind of antibody induction compared with no induction (1/22 (5%) versus 0/22 (0%), (Analysis 1.8 (1 study, 44 participants) RR 3.00, 95% CI 0.13 to 69.87). This was confirmed using Fisher's exact test (P = 1.0)
Cancer
Hartvig 2008 reported no significant difference in the number of patients diagnosed with cancer between the antibody induction group compared with the no induction group (8/22 (36%) versus 3/22 (14%), (Analysis 1.9 (1 study, 44 participants): RR 2.67, 95% CI 0.81 to 8.75). This was confirmed using Fisher's exact test (P = 0.16). The eight malignancies reported in antibody induction group included three non‐small cell lung cancers, one prostate cancer, one squamous cell nasopharynx cancer, and four skin cancers. There were three malignancies reported among control group: one non‐small cell lung cancer and two skin cancers.
Kidney injury requiring haemodialysis
Kidney injury requiring haemodialysis was not reported.
Polyclonal T‐cell antibody versus no induction
Chaparro 1999 (60 participants) compared ALG versus placebo, and Hartvig 2008 (44 participants) compared ATG versus no intervention. Conte 2010 (36 participants) randomised patients to three groups: ATG, daclizumab or no intervention. The 15 patients who received daclizumab in Conte 2010 were excluded from the analyses.
Mortality
There was no significant difference in the number of deaths between patients treated with polyclonal antibody induction compared with no induction (29/67 (43%) versus 26/58 (45%), (Analysis 2.1 (3 studies, 125 participants): RR 0.94, 95% CI 0.66 to 1.31; I² = 0%). Analysis showed that trial sequential monitoring boundaries were not broken by the cumulative Z‐curve, and the required information size of 935 patients was not achieved.
Acute rejection
There was no significant difference in the number of patients experiencing acute rejection between those treated with polyclonal T‐cell antibody induction compared with no induction (21/67 (31%) versus 28/58 (48%), (Analysis 2.2 (3 studies, 125 participants): RR 0.68, 95% CI 0.44 to 1.04; I² = 75%). Analysis showed that trial sequential monitoring boundaries were not broken by the cumulative Z‐curve, and the required information size of 3344 patients was not achieved.
Adverse events
Hartvig 2008 reported that no other adverse events occurred in any of the treatment groups (Analysis 2.3). Chaparro 1999 and Conte 2010 did not report adverse events. Therefore, only the zero event study (Hartvig 2008) contributed data for analysis, and consequently, a meta‐analysis using zero event correction was not conducted.
Quality of life
Quality of life measures were not reported.
Infection
There was no significant difference in the number of infections between patients treated with polyclonal T‐cell antibody induction compared with no induction (36/56 (64%) versus 22/48 (46%), (Analysis 2.4 (2 studies, 104 participants): RR 1.40, 95% CI 0.97 to 2.01; I² = 0%).
Pneumonia (viral, bacterial, and fungal)
There was no significant difference in the number of patients with pneumonia between those treated with polyclonal T‐cell antibody induction compared with no induction (23/45 (51%) versus 14/36 (39%), (Analysis 2.5 (2 studies, 81 participants): RR 1.40, 95% CI 0.97 to 2.01; I² = 92%).
Cytomegalovirus infection
There was no significant difference in the number of patients with cytomegalovirus infection between those treated with polyclonal T‐cell antibody induction compared with no induction (19/33 (58%) versus 15/32 (47%), (Analysis 2.6 (2 studies, 65 participants): RR 1.23, 95% CI 0.77 to 1.97; I² = 0%).
Bronchiolitis obliterans syndrome
There was no significant difference in the number of patients with bronchiolitis obliterans syndrome between those treated with polyclonal T‐cell antibody induction compared with no induction (28/67 (42%) versus 31/58 (53%), (Analysis 2.7 (3 studies, 125 participants): RR 0.76, 95% CI 0.56 to 1.05; I² = 0%).
Post‐transplantation lymphoproliferative disease
Hartvig 2008 reported no significant difference in the number of patients diagnosed with PTLD between those treated with polyclonal T‐cell antibody induction compared with no induction (1/22 (5%) versus 0/22 (0%), (Analysis 2.8 (1 study, 44 participants): RR 3.00, 95% CI 0.13 to 69.87). This was confirmed using Fisher's exact test (P = 1.0).
Cancer
Hartvig 2008 reported no significant difference in the number of patients diagnosed with cancer between the polyclonal T‐cell antibody induction group compared with no induction (8/22 (36%) versus 3/22 (14%), (Analysis 2.9 (1 study, 44 participants): RR 2.67, 95% CI 0.81 to 8.75). This was confirmed using Fisher's exact test (P = 0.16). The eight malignancies reported in antibody induction group included three non‐small cell lung cancers, one prostate cancer, one squamous cell nasopharynx cancer, and four skin cancers. There were three malignancies reported among control group that included one non‐small cell lung cancer and two skin cancers.
Kidney injury requiring haemodialysis
Kidney injury requiring haemodialysis was not reported.
Interleukin‐2 receptor antagonist versus no induction
Conte 2010 (36 participants) randomised patients to three groups: ATG, daclizumab or no intervention. The 11 patients who received ATG were excluded from the analyses.
Mortality
Conte 2010 reported no significant difference in the number of deaths among patients who received IL‐2RA compared with those who received no induction therapy (4/15 (27%) versus 4/10 (40%), (Analysis 3.1 (1 study, 25 participants): RR 0.67, 95% CI 0.22 to 2.07). This was confirmed using Fisher's exact test (P = 0.67). Analysis showed that trial sequential monitoring boundaries were not broken by the cumulative Z‐curve, and the required information size of 1131 patients was not achieved.
Acute rejection
Conte 2010 reported no significant difference in the number of patients experiencing at least one episode of rejection between those treated with IL‐2RA compared with no induction (8/15 (53%) versus 5/10 (50%), (Analysis 3.2 (1 study, 25 participants): RR 1.07, 95% CI 0.49 to 2.33). This was confirmed using Fisher's exact test (P = 1.0). Analysis showed that trial sequential monitoring boundaries were not broken by the cumulative Z‐curve, and the required information size of 778 patients was not achieved.
Adverse events
Adverse events were not reported.
Quality of life
Quality of life measures were not reported.
Infection
Infection rates were not reported.
Pneumonia (viral, bacterial, or fungal)
Conte 2010 reported no significant difference in the number of patients with pneumonia between those treated with IL‐2RA compared with no induction (10/15 (67%) versus 10/10 (100%), (Analysis 3.3 (1 study, 25 participants): RR 0.69, 95% CI 0.47 to 1.00). This was confirmed using Fisher's exact test (P = 0.06).
Cytomegalovirus infection
Conte 2010 reported no significant difference in the number of patients with cytomegalovirus infection between those treated with IL‐2RA compared with no induction (6/15 (40%) versus 5/10 (50%), (Analysis 3.4 (1 study, 25 participants): RR 0.80, 95% CI 0.33 to 1.92). This was confirmed using Fisher's exact test (P = 0.70).
Bronchiolitis obliterans syndrome
Conte 2010 reported no significant difference in the number of patients with bronchiolitis obliterans syndrome between those treated with IL‐2RA compared with no induction (2/15 (13%) versus 4/10 (40%), (Analysis 3.5 (1 study, 25 participants): RR 0.33, 95% CI 0.07 to 1.49). This was confirmed using Fisher's exact test (P = 0.18).
Post‐transplantation lymphoproliferative disease
PTLD was not reported.
Cancer
Cancers were not reported.
Kidney injury requiring haemodialysis
Kidney injury requiring haemodialysis was not reported.
Polyclonal T‐cell antibody versus muromonab‐CD3
Brock 2001 (64 participants) compared ATG versus muromonab‐CD3.
Mortality
Brock 2001 did not report sufficient mortality data to enable statistical analysis. Two year survival for the entire cohort was 68%, with no differences observed in survival among the three induction groups: the ATG and muromonab‐CD3 groups (both of which were randomised), and non‐randomised daclizumab group.
Acute rejection
Acute rejection was not sufficiently reported to enable statistical analysis. Brock 2001 reported that there was no difference in freedom from acute rejection episodes of grade A2 or greater among the three groups (randomised ATG and muromonab‐CD3 groups; non‐randomised daclizumab group).
Adverse events
Brock 2001 reported drug‐specific adverse effects were more common in the ATG group compared with the muromonab‐CD3 group (25/34 (74%) versus 12/30 (40%), (Analysis 4.1 (1 study, 64 participants): RR 1.84, 95% CI 1.13 to 2.98). This was confirmed using Fisher's exact test (P = 0.01). Cytokine release syndrome occurred in 12/30 (40%) patients in the muromonab‐CD3 group, among whom it was associated with hypoxia (5/30, 17%), hypotension (5/30, 17%), and rigor (1/30, 3%). Thrombocytopenia occurred in 25/34 (74%) patients in the ATG group.
Quality of life
Quality of life measures were not reported.
Infection
Brock 2001 reported no significant difference in the number of infections between patients treated with ATG compared with muromonab‐CD3 (25/34 (74%) versus 23/30 (77%), (Analysis 4.2 (1 study, 64 participants): RR 0.96, 95% CI 0.72 to 1.27). This was confirmed using Fisher's exact test (P = 1.0).
The incidences of pneumonia or cytomegalovirus infection were not reported.
Bronchiolitis obliterans syndrome
Brock 2001 reported no significant difference in the number of patients with bronchiolitis obliterans syndrome between those treated with ATG compared with muromonab‐CD3 (5/34 (15%) versus 7/30 (23%), (Analysis 4.3 (1 study, 64 participants): RR 0.63, 95% CI 0.22 to 1.78). This was confirmed using Fisher's exact test (P = 0.52).
Post‐transplantation lymphoproliferative disease
Brock 2001 reported no significant difference in the number of patients diagnosed with PTLD between those treated with ATG compared with muromonab‐CD3 (2/34 (6%) versus 2/30 (7%), (Analysis 4.4 (1 study, 64 participants): RR 0.88; 95% CI 0.13 to 5.88). This was confirmed using Fisher's exact test (P = 1.0).
Cancer
Cancers were not reported.
Kidney failure requiring haemodialysis
Kidney failure requiring haemodialysis was not reported.
Polyclonal T‐cell antibody versus interleukin‐2 receptor antagonist
Mullen 2007 (50 participants) compared ATG versus daclizumab; Senn 2001 (24 participants) compared ATG versus basiliximab; and Conte 2010 (36 participants) randomised patients to three groups: ATG, daclizumab or no intervention. The 10 patients in Conte 2010 not receiving T‐cell antibody induction were excluded from the analyses.
Mortality
There was no significant differences in the number of deaths between patients treated with ATG induction compared with IL‐2RA induction (7/47 (15%) versus 6/53 (11%), (Analysis 5.1 (3 studies, 100 participants): RR 1.41, 95% CI 0.54 to 3.70; I² = 0%). Analysis showed that trial sequential monitoring boundaries were not broken by the cumulative Z‐curve, and the required information size of 5787 patients was not obtained.
Acute rejection
There was no significant difference in the number of patients experiencing acute rejection between those treated with polyclonal antibody induction compared with IL‐2RA (25/36 (69%) versus 21/40 (53%), (Analysis 5.2 (2 studies, 76 participants): RR 1.35, 95% CI 0.94 to 1.94; I² = 0%). Analysis showed that trial sequential monitoring boundaries were not broken by the cumulative Z‐curve, and the required information size of 698 patients was not obtained.
Adverse events
Mullen 2007 reported that one drug‐related adverse event occurred in the ATG group that involved lymphopenia and thrombocytopenia (Analysis 5.3). ATG infusion was temporarily discontinued.
Quality of life
Quality of life measures were not reported.
Infection
Mullen 2007 reported no significant difference in the number of infections between patients treated with ATG compared with IL‐2RA (20/25 (80%) versus 22/25 (88%), (Analysis 5.4 (1 study, 50 participants): RR 0.91, 95% CI 0.71 to 1.16). This was confirmed using Fisher's exact test (P = 0.70).
Pneumonia (viral, bacterial, or fungal)
Conte 2010 reported no significant difference in the number of patients with pneumonia between those treated with ATG compared with IL‐2RA (8/11 (73%) versus 10/15 (67%), (Analysis 5.5 (1 study, 26 participants): RR 1.09, 95% CI 0.66 to 1.81). This was confirmed using Fisher's exact test (P = 1.0).
Cytomegalovirus infection
There was no significant difference in the number of patients with cytomegalovirus infection between those treated with ATG compared with IL‐2RA (10/36 (28%) versus 18/40 (45%), (Analysis 5.6 (2 studies, 76 participants): RR 0.69, 95% CI 0.17 to 2.88; I² = 80%).
Bronchiolitis obliterans syndrome
There was no significant difference in the number of patients with bronchiolitis obliterans syndrome between those treated with ATG compared with IL‐2RA (4/36 (11%) versus 3/40 (8%), (Analysis 5.7 (2 studies, 76 participants): RR 1.70, 95% CI 0.42 to 6.79; I² = 0%).
Post‐transplantation lymphoproliferative disease
Mullen 2007 reported no significant difference in the number of patients diagnosed with PTLD between those treated with ATG induction and the IL‐2RA induction (1/25 (4%) versus 1/25 (4%), (Analysis 5.8 (1 study, 50 participants): RR 1.00, 95% CI 0.07 to 15.12). This was confirmed using Fisher's exact test (P = 1.0).
Cancer
Mullen 2007 reported no malignancies were seen in either the ATG induction or IL‐2RA induction groups. The only study contributing data for this outcome reported no events, and therefore, meta‐analysis was not undertaken.
Kidney failure requiring haemodialysis
Kidney failure requiring haemodialysis was not reported.
Subgroup analyses
We performed subgroup analyses on ATG type (rabbit versus horse) compared with IL‐2RA on several outcome measures: mortality, acute rejection, bronchiolitis obliterans syndrome, and cytomegalovirus infection. We found no significant differences between type of ATG when applying the test of interaction regarding mortality, acute rejection and bronchiolitis obliterans syndrome. Horse ATG may be better in preventing cytomegalovirus infection than rabbit ATG (P = 0.03).
We conducted subgroup analyses on IL‐2RA type (basiliximab versus daclizumab) compared with ATG on mortality, and found no significant differences between IL‐2RAs when applying the test of interaction.
Other subgroup analyses
We were unable to perform planned subgroup analyses on risk of bias (high versus low) because all included studies were assessed as high risk of bias. Likewise, subgroup analysis on timing (early versus late) calcineurin inhibitor initiation could not be undertaken because this outcome was not reported.
Assessment of harm in non‐randomised controlled studies
We identified eight non‐RCTs that were assessed for the risk of harm (Barlow 2001; Borro 2005; Burton 2006; Garrity 2001; Hachem 2005; Lischke 2007; van Loenhout 2010; Marom 2001) (Table 1). We assessed numbers of patients with infection, cytomegalovirus infection, PTLD, and other adverse effects. Overall, no clear harmful effects were identified regarding comparisons of types of induction therapies, or induction therapy type compared with controls.
| Study | Participants | Study groups | PTLD | Infection | CMV | Other adverse events |
| 63 | Muromonab‐CD3: 38 ATG: 25 | Not reported | No difference between groups | No difference between groups | Not reported | |
| 28 | Daclizumab: 15 Control: 13 | Not observed | Fungal Daclizumab: 1 (7%) Control: 2 (15%) Bacterial Daclizumab: 4 (27%) Control: 2 (15%) | Daclizumab: 4 (27%) Control: 5 (38%) | Not observed | |
| 335 | ATG: 151 Daclizumab: 151 | ATG: 8 (5%) Daclizumab: 2 (1%) | Not reported | No difference between groups | Not reported | |
| 61 | Daclizumab: 27 Control: 34 | Daclizumab: 1 (4%) Control: 1 (3%) | Fungal Daclizumab: 5 (19%) Control: 5 (15%) | Daclizumab: 5 (19%) Control: 8 (24%) | Not reported | |
| 157 | ATG: 75 Basiliximab: 82 | ATG: 0.53 cases/100 patient‐years Basiliximab: 3 cases/100 patient‐years | Not reported | CMV‐viraemia ATG: 15.1 episodes/100 patient‐months Basiliximab: 15.6 episodes/100 patient‐months | Not reported | |
| 25 | ATG: 12 Daclizumab: 13 | No PTLD | ATG: 10 (83%) Daclizumab: 6 (46%) | No difference between groups | Thrombocytopenia ATG: 9 (75%) Daclizumab: 0 (0%) | |
| 86 | Daclizumab: 43 Control: 43 | Not observed | Not reported | Not reported | Not reported | |
| 40 | Alemtuzumab: 20 Control: 20 | Not reported | No difference between groups | Not reported | Not observed |
ATG ‐ antithymocyte globulin; CMV ‐ cytomegalovirus; PTLD ‐ post‐transplant lymphoproliferative disease
Discussion
Summary of main results
This review identified six studies (278 participants) that assessed the effects of different types of T‐cell antibody induction in lung transplant recipients. All included studies were assessed at high risk of bias.
Overall our meta‐analyses did not find any statistically significant differences between any of the randomised groups regarding mortality, acute rejection, infection, pneumonia, cytomegalovirus infection, bronchiolitis obliterans syndrome, PTLD, or cancer.
The only study comparing ATG with muromonab‐CD3 seemed to show an increase in adverse events in the ATG group; however, trial sequential analysis could not exclude random error (Conte 2010).
None of the studies reported on quality of life or kidney failure requiring haemodialysis.
Findings were confirmed when the fixed‐effect model was applied to the meta‐analyses. The required information size was not obtained in any trial sequential analyses for the primary outcome measures. Absence of evidence however does not necessarily mean absence of effect.
Overall completeness and applicability of evidence
We examined the evidence from six RCTs that investigated the use of T‐cell antibody induction for lung transplant recipients. We were unable to obtain data relating to all pre‐defined outcome measures because they were not all reported in the included studies.
Overall, reporting in the included studies was suboptimal: five studies reported adequately on mortality; four on acute rejection; four on infection; and five on bronchiolitis obliterans syndrome. Only two studies reported on drug‐related adverse events. None of the studies reported on quality of life or kidney failure requiring haemodialysis.
Not all types of T‐cell antibody induction currently available have been studied in randomised studies. Alemtuzumab for induction after lung transplantation has been introduced during the last decade, and is now used for almost 10% of all lung transplant recipients. However, no evidence from randomised studies regarding alemtuzumab was identified. IL‐2RA were found to be the most commonly used type of induction therapy, used in over 40% of all lung transplant recipients. Nevertheless only one included randomised study with 25 patients investigated the use of IL‐2RA compared with no intervention. A study that compared IL‐2RA with no intervention has been completed, but contact with the investigators indicated that results were not yet available (Waddell 2006).
Quality of the evidence
We conducted this review in accordance with the requirements in The Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and conducted trial sequential analysis (Wetterslev 2008; TSA 2011).
The quality and quantity of available evidence limited our findings and interpretations. Very limited numbers of participants were included in the studies, and hence, risks of random errors potentially explain occasional positive findings in individual studies. Additionally, study participants may not be representative of the general patient population.
Follow‐up in five studies was between six months and two years; and eight years in one study. We therefore were unable to elicit evidence relating to longer‐term (greater than two years) effects of T‐cell antibody induction on outcome measures. Long‐term effects in terms of mortality, bronchiolitis obliterans syndrome, infection, and cancer would be particularly valuable.
We explored the presence of statistical heterogeneity using the Chi² test and measured heterogeneity using the I² test (Higgins 2003). The Chi² test is low powered in meta‐analyses where studies are small or few in number, as in this review. This means that while a statistically significant result may indicate a problem with heterogeneity, a non‐significant result must not be taken as evidence of homogeneity. To reflect our concern with heterogeneity, we looked at both fixed‐effect and random‐effects models to provide more conservative effect estimates. No differences were seen between fixed‐effect and random‐effects models for any of the primary outcome measures considered in this review.
Precision of our results was influenced because many outcomes planned for meta‐analyses includes few patients and events, and thus, have wide confidence intervals around the effect estimate.
Potential biases in the review process
Bias is known to impact on the estimated intervention effect, and studies assessed at high risk of bias tend to overestimate beneficial intervention effects (Kjaergard 2001; Moher 1998; Schulz 1995). Of the six included studies, reporting was suboptimal: allocation concealment was not reported in any of the included studies; adequate allocation sequence generation was reported by one study; participant blinding was reported by one study; one was blinded for the pathologist who examined transbronchial biopsies for rejection. Reporting of incomplete outcome data was adequate in four studies, and all reported on reasonably expected outcome measures. Four studies appeared to be free of other components that could put the study at risk of bias, and one was unclear. Accordingly, all studies were considered to be at high risk of bias, and estimated intervention effects may therefore be due to systematic errors.
The risk of random error is higher among data from small studies. Studies need to be sufficiently large to reduce the risk of random error and increase the chance of observing a true intervention effect (Wetterslev 2008). To address these issues, we also conducted trial sequential analysis. Trial sequential analysis is a statistical method that assesses risk of random error caused by sparse data and formal or informal repetitive testing of accumulated data. Trial sequential analysis of outcome measures in this review showed that the required information size was not reached. Hence, we were unable to determine whether there may be beneficial or harmful effects associated with the use of antibody induction or relative superiority of any antibody over another.
Agreements and disagreements with other studies or reviews
Data from the International Society for Heart and Lung Transplantation registry, which are based on nearly 11,000 lung recipients who received lung transplants between January 2000 and June 2009, showed that T‐cell antibody induction appeared to have a favourable effect on survival (Christie 2011). Due to the observational nature of these data, findings should be interpreted with caution because they were not adjusted for diagnosis category, age, centre, or other potentially confounding factors. The reduced mortality observed in the registry data could not be confirmed in our meta‐analyses. Furthermore, the registry data showed that compared with other types of induction therapy, IL‐2RA induction was associated with a lower incidence of acute rejection during the first year following transplantation (Christie 2011). The lower rejection rates among lung transplant recipients who were treated with IL‐2RA induction therapy appeared to be similar across age groups, despite apparent differences in rejection rates with other induction strategies by recipient age category (Christie 2011).
Using data from the same registry, Hachem 2008 found that IL‐2RA induction therapy for single and double lung transplant recipients and induction with ATG for double lung transplant recipients was associated with lower mortality. We were unable to confirm this reduction in mortality and acute rejection associated with the use of IL‐2RA in our meta‐analyses.
Large cohort studies conducted by Burton 2006 and Hachem 2005 compared ATG and IL‐2RA. Burton 2006 compared induction using rabbit ATG with daclizumab induction in 335 lung transplant recipients. Patients who received ATG had a statistically significant lower incidence of acute rejection compared with patients who were treated with daclizumab (Burton 2006). Hachem 2005 compared induction using horse ATG with basiliximab induction in 157 lung transplant recipients. Lung transplant recipients with severe ischaemia‐reperfusion injury after transplantation, and those who were serologically mismatched for cytomegalovirus, were excluded from ATG induction therapy (Hachem 2005). Acute rejection and bronchiolitis obliterans syndrome occurred less often in the ATG group compared with the basiliximab group (Hachem 2005).
Findings similar to those reported by Burton 2006 and Hachem 2005 showing less rejection associated with ATG compared with IL‐2RA were not found when data from the International Society for Heart and Lung Transplantation registry were analysed (Christie 2011). Likewise, our meta‐analyses could not confirm these findings.
Traditionally, immunosuppressive therapy for lung transplantation has gained much knowledge from the reported experiences of other types of organ transplantation. A Cochrane review by Webster 2010 that included 71 studies reporting data on 10,537 patients investigated the use of IL‐2RA for kidney transplant recipients. Webster 2010 found that compared with placebo, IL‐2RA reduced graft loss, including death, by 25% at six months and one year, but not beyond (Webster 2010). Furthermore, compared with placebo, IL‐2RA reduced biopsy‐proven acute rejection (RR 0.75, 95% CI 0.58 to 0.98) and cytomegalovirus disease (RR 0.81, 95% CI 0.68 to 0.97) in kidney transplant recipients (Webster 2010). Where IL‐2RA was compared with ATG in kidney transplant recipients, biopsy‐proven acute rejection at one year was increased in the IL‐2RA group by 30%, but incidence of malignancies (RR 0.25, 95% CI 0.07 to 0.87) and cytomegalovirus disease (RR 0.68, 95 % CI 0.50 to 0.97) were reduced when IL‐2RA was compared with ATG (Webster 2010).
In a recent Cochrane review (Penninga 2012a), we compared antibody induction versus no induction for liver transplant recipients in 17 studies with a total of 1951 patients. Antibody induction may reduce acute rejection when compared with no antibody induction. No other clear benefits or harms were associated with the use of antibody induction compared with no antibody induction (Penninga 2012a).
Furthermore, we reported the use of antibody induction therapy compared with corticosteroid for liver transplant recipients. Our review included 10 studies that presented data from 1589 participants (Penninga 2012b). Antibody induction seems to reduce diabetes mellitus and may reduce cytomegalovirus infection when compared with corticosteroid induction. No other clear benefits or harms were associated with the use of antibody induction compared with corticosteroid induction (Penninga 2012b).
Our earlier Cochrane review (Penninga 2010) investigated the use of antibody induction for heart transplant recipients. This review included 22 studies that presented data from 1427 participants. This review demonstrated that compared with placebo, IL‐2RA induction may reduce acute rejection when meta‐analysed using a fixed‐effect model; however, this effect did not occur using a random‐effects model. Polyclonal antibodies may be superior in reducing acute rejection compared with IL‐2RA for heart transplant recipients, but not for other outcomes. The review found no significant differences regarding mortality, infections, and malignancy (Penninga 2010).
Overall, potential advantages of some antibody types concerning certain outcome measures in other solid organ transplant recipients were not found in lung transplant recipients. Whether this is due to the limited numbers of patients and events, systematic errors, design errors, or organ‐specific differences is currently unclear.
Study flow diagram
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Any induction versus no induction; mortality: trial sequential analysis of the effect of induction versus no induction on mortality based on three studies (140 participants). The required information size of 935 patients was calculated based on type I error of 5%, type II error of 20%, risk reduction of 20%, and information size was adjusted for heterogeneity (I² = 0%)
Comparison 1 Induction versus no induction, Outcome 1 Mortality.
Comparison 1 Induction versus no induction, Outcome 2 Acute rejection grade II or higher.
Comparison 1 Induction versus no induction, Outcome 3 Adverse events.
Comparison 1 Induction versus no induction, Outcome 4 Infection.
Comparison 1 Induction versus no induction, Outcome 5 Pneumonia.
Comparison 1 Induction versus no induction, Outcome 6 CMV infection.
Comparison 1 Induction versus no induction, Outcome 7 Bronchiolitis obliterans syndrome.
Comparison 1 Induction versus no induction, Outcome 8 Post‐transplantation lymphoproliferative disease (PTLD).
Comparison 1 Induction versus no induction, Outcome 9 Cancer.
Comparison 2 Polyclonal antibody versus no induction, Outcome 1 Mortality.
Comparison 2 Polyclonal antibody versus no induction, Outcome 2 Acute rejection grade II or higher.
Comparison 2 Polyclonal antibody versus no induction, Outcome 3 Adverse events.
Comparison 2 Polyclonal antibody versus no induction, Outcome 4 Infection.
Comparison 2 Polyclonal antibody versus no induction, Outcome 5 Pneumonia.
Comparison 2 Polyclonal antibody versus no induction, Outcome 6 CMV infection.
Comparison 2 Polyclonal antibody versus no induction, Outcome 7 Bronchiolitis obliterans syndrome.
Comparison 2 Polyclonal antibody versus no induction, Outcome 8 Post‐transplantation lymphoproliferative disease (PTLD).
Comparison 2 Polyclonal antibody versus no induction, Outcome 9 Cancer.
Comparison 3 Interleukin‐2 receptor antagonist versus no induction, Outcome 1 Mortality.
Comparison 3 Interleukin‐2 receptor antagonist versus no induction, Outcome 2 Acute rejection.
Comparison 3 Interleukin‐2 receptor antagonist versus no induction, Outcome 3 Pneumonia.
Comparison 3 Interleukin‐2 receptor antagonist versus no induction, Outcome 4 CMV infection.
Comparison 3 Interleukin‐2 receptor antagonist versus no induction, Outcome 5 Bronchiolitis obliterans syndrome.
Comparison 4 Polyclonal antibody versus muromonab‐CD3, Outcome 1 Adverse events.
Comparison 4 Polyclonal antibody versus muromonab‐CD3, Outcome 2 Infection.
Comparison 4 Polyclonal antibody versus muromonab‐CD3, Outcome 3 Bronchiolitis obliterans syndrome.
Comparison 4 Polyclonal antibody versus muromonab‐CD3, Outcome 4 Post‐transplantation lymphoproliferative disease (PTLD).
Comparison 5 Polyclonal antibody versus interleukin‐2 receptor antagonist, Outcome 1 Mortality.
Comparison 5 Polyclonal antibody versus interleukin‐2 receptor antagonist, Outcome 2 Acute rejection.
Comparison 5 Polyclonal antibody versus interleukin‐2 receptor antagonist, Outcome 3 Adverse events.
Comparison 5 Polyclonal antibody versus interleukin‐2 receptor antagonist, Outcome 4 Infection.
Comparison 5 Polyclonal antibody versus interleukin‐2 receptor antagonist, Outcome 5 Pneumonia.
Comparison 5 Polyclonal antibody versus interleukin‐2 receptor antagonist, Outcome 6 CMV infection.
Comparison 5 Polyclonal antibody versus interleukin‐2 receptor antagonist, Outcome 7 Bronchiolitis obliterans syndrome.
Comparison 5 Polyclonal antibody versus interleukin‐2 receptor antagonist, Outcome 8 Post‐transplantation lymphoproliferative disease (PTLD).
Comparison 5 Polyclonal antibody versus interleukin‐2 receptor antagonist, Outcome 9 Cancer.
| T‐cell antibody induction compared with no antibody induction for lung transplant recipients | ||||||
| Patient or population: lung transplant recipients | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No antibody induction | Antibody induction | |||||
| Mortality | Study population | RR 0.99 | 140 (3) | ⊕⊕⊕⊝ | ||
| 448 per 1000 | 444 per 1000 | |||||
| Moderate | ||||||
| 400 per 1000 | 396 per 1000 | |||||
| Acute rejection grade II or higher | Study population | RR 0.66 | 140 (3) | ⊕⊕⊕⊝ | ||
| 483 per 1000 | 319 per 1000 | |||||
| Moderate | ||||||
| 500 per 1000 | 330 per 1000 | |||||
| Infection | Study population | RR 1.4 | 104 (2) | ⊕⊕⊕⊝ | ||
| 458 per 1000 | 642 per 1000 | |||||
| Moderate | ||||||
| 458 per 1000 | 641 per 1000 | |||||
| Bronchiolitis obliterans syndrome | Study population | RR 0.77 | 140 (3) | ⊕⊕⊕⊝ | ||
| 534 per 1000 | 412 per 1000 | |||||
| Moderate | ||||||
| 400 per 1000 | 308 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹ All studies were assessed to be at high risk of bias using the Cochrane risk of bias tool | ||||||
| Polyclonal T‐cell antibody compared with no antibody induction for lung transplant recipients | ||||||
| Patient or population: lung transplant recipients | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No antibody induction | Polyclonal antibody | |||||
| Mortality | Study population | RR 1.02 | 125 (3) | ⊕⊕⊕⊝ | ||
| 448 per 1000 | 457 per 1000 | |||||
| Moderate | ||||||
| 400 per 1000 | 408 per 1000 | |||||
| Acute rejection grade II or higher | Study population | RR 0.68 | 125 (3) | ⊕⊕⊕⊝ | ||
| 483 per 1000 | 328 per 1000 | |||||
| Moderate | ||||||
| 500 per 1000 | 340 per 1000 | |||||
| Infection | Study population | RR 1.4 | 104 (2) | ⊕⊕⊕⊝ | ||
| 458 per 1000 | 642 per 1000 | |||||
| Moderate | ||||||
| 458 per 1000 | 641 per 1000 | |||||
| Bronchiolitis obliterans syndrome | Study population | RR 0.81 | 125 (3) | ⊕⊕⊕⊝ | ||
| 534 per 1000 | 433 per 1000 | |||||
| Moderate | ||||||
| 400 per 1000 | 324 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹ All studies were assessed to be at high risk of bias using the Cochrane risk of bias tool | ||||||
| IL‐2 receptor antagonist induction compared with no antibody induction for lung transplant recipients | ||||||
| Patient or population: lung transplant recipients | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No antibody induction | IL‐2RA induction | |||||
| Mortality | Study population | RR 0.67 | 25 (1) | ⊕⊕⊕⊝ | ||
| 400 per 1000 | 268 per 1000 | |||||
| Moderate | ||||||
| 400 per 1000 | 268 per 1000 | |||||
| Acute rejection | Study population | RR 1.07 | 25 (1) | ⊕⊕⊕⊝ | ||
| 500 per 1000 | 535 per 1000 | |||||
| Moderate | ||||||
| 500 per 1000 | 535 per 1000 | |||||
| Bronchiolitis obliterans syndrome | Study population | RR 0.33 | 25 (1) | ⊕⊕⊕⊝ | ||
| 400 per 1000 | 132 per 1000 | |||||
| Moderate | ||||||
| 400 per 1000 | 132 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹ All studies were assessed to be at high risk of bias using the Cochrane risk of bias tool | ||||||
| Polyclonal T‐cell antibody induction compared with IL‐2RA induction for lung transplant recipients | ||||||
| Patient or population: lung transplant recipients | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| IL‐2RA induction | Polyclonal antibody induction | |||||
| Mortality | Study population | RR 1.41 | 100 (3) | ⊕⊕⊕⊝ | ||
| 113 per 1000 | 160 per 1000 | |||||
| Moderate | ||||||
| 77 per 1000 | 109 per 1000 | |||||
| Acute rejection | Study population | RR 1.33 | 76 (2) | ⊕⊕⊕⊝ | ||
| 525 per 1000 | 698 per 1000 | |||||
| Moderate | ||||||
| 527 per 1000 | 701 per 1000 | |||||
| Infection | Study population | RR 0.91 | 50 (1) | ⊕⊕⊕⊝ | ||
| 880 per 1000 | 801 per 1000 | |||||
| Moderate | ||||||
| 880 per 1000 | 801 per 1000 | |||||
| Bronchiolitis obliterans syndrome | Study population | RR 1.66 | 76 (2) | ⊕⊕⊕⊝ | ||
| 75 per 1000 | 124 per 1000 | |||||
| Moderate | ||||||
| 87 per 1000 | 144 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹ All studies were assessed to be at high risk of bias using the Cochrane risk of bias tool | ||||||
| Study | Participants | Study groups | PTLD | Infection | CMV | Other adverse events |
| 63 | Muromonab‐CD3: 38 ATG: 25 | Not reported | No difference between groups | No difference between groups | Not reported | |
| 28 | Daclizumab: 15 Control: 13 | Not observed | Fungal Daclizumab: 1 (7%) Control: 2 (15%) Bacterial Daclizumab: 4 (27%) Control: 2 (15%) | Daclizumab: 4 (27%) Control: 5 (38%) | Not observed | |
| 335 | ATG: 151 Daclizumab: 151 | ATG: 8 (5%) Daclizumab: 2 (1%) | Not reported | No difference between groups | Not reported | |
| 61 | Daclizumab: 27 Control: 34 | Daclizumab: 1 (4%) Control: 1 (3%) | Fungal Daclizumab: 5 (19%) Control: 5 (15%) | Daclizumab: 5 (19%) Control: 8 (24%) | Not reported | |
| 157 | ATG: 75 Basiliximab: 82 | ATG: 0.53 cases/100 patient‐years Basiliximab: 3 cases/100 patient‐years | Not reported | CMV‐viraemia ATG: 15.1 episodes/100 patient‐months Basiliximab: 15.6 episodes/100 patient‐months | Not reported | |
| 25 | ATG: 12 Daclizumab: 13 | No PTLD | ATG: 10 (83%) Daclizumab: 6 (46%) | No difference between groups | Thrombocytopenia ATG: 9 (75%) Daclizumab: 0 (0%) | |
| 86 | Daclizumab: 43 Control: 43 | Not observed | Not reported | Not reported | Not reported | |
| 40 | Alemtuzumab: 20 Control: 20 | Not reported | No difference between groups | Not reported | Not observed | |
| ATG ‐ antithymocyte globulin; CMV ‐ cytomegalovirus; PTLD ‐ post‐transplant lymphoproliferative disease | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mortality Show forest plot | 3 | 140 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.67, 1.27] |
| 2 Acute rejection grade II or higher Show forest plot | 3 | 140 | Risk Ratio (M‐H, Random, 95% CI) | 0.68 [0.33, 1.41] |
| 3 Adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Infection Show forest plot | 2 | 104 | Risk Ratio (M‐H, Random, 95% CI) | 1.40 [0.97, 2.01] |
| 5 Pneumonia Show forest plot | 2 | 96 | Risk Ratio (M‐H, Random, 95% CI) | 1.38 [0.18, 10.63] |
| 6 CMV infection Show forest plot | 2 | 80 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [0.73, 1.80] |
| 7 Bronchiolitis obliterans syndrome Show forest plot | 3 | 140 | Risk Ratio (M‐H, Random, 95% CI) | 0.74 [0.51, 1.07] |
| 8 Post‐transplantation lymphoproliferative disease (PTLD) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9 Cancer Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mortality Show forest plot | 3 | 125 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.68, 1.31] |
| 1.1 ALG | 1 | 60 | Risk Ratio (M‐H, Random, 95% CI) | 1.53 [0.59, 3.93] |
| 1.2 Rabbit ATG | 2 | 65 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.63, 1.25] |
| 2 Acute rejection grade II or higher Show forest plot | 3 | 125 | Risk Ratio (M‐H, Random, 95% CI) | 0.73 [0.30, 1.79] |
| 2.1 ALG | 1 | 60 | Risk Ratio (M‐H, Random, 95% CI) | 0.48 [0.18, 1.29] |
| 2.2 Rabbit ATG | 2 | 65 | Risk Ratio (M‐H, Random, 95% CI) | 0.87 [0.25, 3.06] |
| 3 Adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.1 Rabbit ATG | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Infection Show forest plot | 2 | 104 | Risk Ratio (M‐H, Random, 95% CI) | 1.40 [0.97, 2.01] |
| 4.1 ALG | 1 | 60 | Risk Ratio (M‐H, Random, 95% CI) | 1.47 [0.91, 2.36] |
| 4.2 Rabbit ATG | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 1.3 [0.73, 2.31] |
| 5 Pneumonia Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 5.1 ALG | 2 | 81 | Risk Ratio (M‐H, Random, 95% CI) | 1.40 [0.23, 8.48] |
| 6 CMV infection Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 6.1 Rabbit ATG | 2 | 65 | Risk Ratio (M‐H, Random, 95% CI) | 1.23 [0.77, 1.97] |
| 7 Bronchiolitis obliterans syndrome Show forest plot | 3 | 125 | Risk Ratio (M‐H, Random, 95% CI) | 0.76 [0.55, 1.05] |
| 7.1 ALG | 1 | 60 | Risk Ratio (M‐H, Random, 95% CI) | 1.15 [0.55, 2.39] |
| 7.2 Rabbit ATG | 2 | 65 | Risk Ratio (M‐H, Random, 95% CI) | 0.68 [0.47, 0.99] |
| 8 Post‐transplantation lymphoproliferative disease (PTLD) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8.1 Rabbit ATG | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9 Cancer Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9.1 Rabbit ATG | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mortality Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 Daclizumab | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Acute rejection Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 Daclizumab | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Pneumonia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.1 Daclizumab | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 CMV infection Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4.1 Daclizumab | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Bronchiolitis obliterans syndrome Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5.1 Daclizumab | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 Horse ATG | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Infection Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 Horse ATG | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Bronchiolitis obliterans syndrome Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.1 Horse ATG | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Post‐transplantation lymphoproliferative disease (PTLD) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4.1 Horse ATG | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mortality Show forest plot | 3 | 100 | Risk Ratio (M‐H, Random, 95% CI) | 1.41 [0.54, 3.70] |
| 1.1 Basiliximab | 1 | 24 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.02, 8.69] |
| 1.2 Daclizumab | 2 | 76 | Risk Ratio (M‐H, Random, 95% CI) | 1.62 [0.58, 4.46] |
| 2 Acute rejection Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 Daclizumab | 2 | 76 | Risk Ratio (M‐H, Random, 95% CI) | 1.35 [0.94, 1.94] |
| 3 Adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.1 Daclizumab | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Infection Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4.1 Basiliximab | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Pneumonia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5.1 Daclizumab | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 CMV infection Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 6.1 Daclizumab | 2 | 76 | Risk Ratio (M‐H, Random, 95% CI) | 0.69 [0.17, 2.88] |
| 7 Bronchiolitis obliterans syndrome Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 7.1 Daclizumab | 2 | 76 | Risk Ratio (M‐H, Random, 95% CI) | 1.70 [0.42, 6.79] |
| 8 Post‐transplantation lymphoproliferative disease (PTLD) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8.1 Daclizumab | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9 Cancer Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9.1 Daclizumab | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
